Alessio Sferrazza

Copper-catalyzed C-C bond formation through C-H functionalization: synthesis of multisubstituted indoles from N-aryl enaminones.

Because of the economic attractiveness and good functional tolerance of copper-catalyzed methods and hence their potential in large-scale applications, during the past few years there have been remarkable advances in the use of copper catalysis in organic synthesis. An impressive number of Ullmann coupling reactions have been described starting from aryl halides and suitable reagents. Recent reports have shown that copper catalysis can also be used in the formation of C heteroatom and C C bonds through selective catalytic activation of aryl C H bonds, a topic of intense current interest that, for the most part, has witnessed the use of palladium-, rhodium-, and ruthenium-based catalysts. In particular, intramolecular copper-catalyzed ortho C H functionalizations through C N and C O bond-forming reactions have been shown to form benzimidazoles and benzoxazoles from amidines and anilides, respectively. Herein, we disclose a new synthesis of multisubstituted indoles from N-aryl enaminones that involves an intramolecular coppercatalyzed aryl C H functionalization through C C bond formation. The indole moiety is prevalent in a vast array of biologically active natural and nonnatural compounds. Consequently, despite the existence of numerous methods for the synthesis of indole derivatives, the development of new, more efficient procedures is a subject of great importance. N-Aryl enaminones 1 were readily prepared through Sonogashira cross-coupling of terminal alkynes with aroyl chlorides, followed by the conjugate addition of anilines with the resultant a,b-ynones. We initiated our study by examining whether the enaminone 1a could be converted into the corresponding indole 2a. Reactions were usually carried out under an atmosphere of air. After an initial screen of copper catalysts (CuSO4, CuCl2, CuI), we found that 2 a could be isolated in 63 % yield by using CuI, Li2CO3, and 1,10-phenanthroline (phen) in dimethyl acetamide (DMA) after 48 h (Table 1, entry 1). Optimization studies were then performed that varied the

Sonogashira cross-coupling of arenediazonium salts.

Arenediazonium salts represent an attractive alternative to aryl halides or triflates because of their higher reactivity, their tolerance of milder conditions, their availability from inexpensive anilines, and because additional base is not required in several applications. Arenediazonium salts have been used in a variety of palladium-catalyzed reactions, including Mizoroki–Heck reactions, Suzuki–Miyaura and Stille crosscoupling reactions, and carbonylation reactions, in the synthesis of sulfinic acids and boronic esters; their use in hydroarylation reactions has also been described. Nevertheless, the alkynylation of arenediazonium salts continues to represent a challenge. After the seminal works of Sonogashira et al. , Heck and Dieck, and Cassar on the alkynylation of aryl iodides and bromides, a great deal of work has been done to extend the scope of the reaction to include an even wider range of reactants; however, the extension of the reaction to arenediazonium salts remains unresolved. To the best of our knowledge, the sole attempt to involve arenediazonium salts in the formation of arylacetylenes was made by GenÞt and co-workers, who obtained only small amounts of the desired cross-coupling derivative by palladium-catalyzed reaction of potassium 1-hexenyltrifluoroborate with para-toluenediazonium tetrafluoroborate. We investigated the reaction using phenylacetylene (1a) and 4-methoxybenzenediazonium tetrafluoroborate (2a) as the model system. No evidence of the formation of cross-coupling product 3a was found using [Pd2(dba)3] (dba = dibenzylideneacetone) or Pd(OAc)2 with a variety of phosphine (PPh3, Xphos, HP(tBu)3BF4) or carbene ligands, generated from 1,3bis(2,6-diisopropylphenyl)imidazolium chloride in the presence of base; a screen of different solvents (MeOH, THF, DME, DMF), in the presence or absence of base (iPr2NEt, K2CO3, Bu4NOAc) and CuI at temperatures ranging from room temperature to 60 8C also afforded no cross-coupled product. In all cases, complex reaction mixtures were obtained, and anisole and 1,4-diphenyl-1,3-diyne were frequently the main by-products. To overcome this limit of the palladium-based chemistry of arenediazonium salts, we reasoned that a strategy in which arylacetylenes are formed by an iododediazoniation reaction, followed by a Sonogashira cross-coupling might be successful. Iododediazoniation is a well-established reaction, and recently remarkable advances have been reported in this area. Nevertheless, no examples of its utilization in a sequential process with a palladium-catalyzed reaction have yet been described. Herein, we show that such a sequential process is indeed possible and report the first utilization of arenediazonium salts in Sonogashira cross-coupling reactions. An initial screen using [PdCl2(PPh3)2], CuI, and Et2NH in MeCN at room temperature showed that 3a could be isolated in 48 % yield in the presence of nBu4NI (1.5 equiv) or NaI (2 equiv; Table 1, entries 1 and 2). Optimization studies were then performed by changing the nature and number of equivalents of the base.

Amphiphile Meets Amphiphile: Beyond the Polar-Apolar Dualism in Ionic Liquid/Alcohol Mixtures.

The mesoscopic morphology of binary mixtures of ethylammonium nitrate (EAN), the protic ionic liquid par excellence, and methanol is explored using neutron/X-ray diffraction and computational techniques. Both compounds are amphiphilic and characterized by an extended hydrogen bonding network: surprisingly, though macroscopically homogeneous, these mixtures turn out to be mesoscopically highly heterogeneous. Our study reveals that even in methanol-rich mixtures, a wide distribution of clusters exists where EAN preserves its bulk, sponge-like morphology. Accordingly methanol does not succeed in fully dissociating the ionic liquid that keeps on organizing in a bulk-like fashion. This behavior represents the premises to the more dramatic phenomenology observed with longer alcohols that eventually phase separate from EAN. These results challenge the commonly accepted polar and apolar moieties segregation in ionic liquids/molecular liquids mixtures and the current understanding of technologically relevant solvation processes.

Heck reaction of arenediazonium salts with N,N-diprotected allylamines. Synthesis of cinnamylamines and indoles.

Novel palladium-catalyzed reactions of arenediazonium tetrafluoroborates with N,N-diprotected allylamines are presented. The reaction of arenediazonium tetrafluoroborates with N,N-(Boc)(2) allylamine allows for an easy approach to cinnamylamines whereas using 2-alkynyl-N-(allyl)trifluoroacetanilides and 2-iodo-N-(allyl)trifluoroacetanilide the reaction provides a useful tool for appending indole rings to aniline fragments.

4-Aryl-2-quinolones via a Domino Heck Reaction/Cyclization Process

The reaction of methyl β-(o-acetamidophenyl)acrylates with aryl iodides in the presence of Pd(OAc) 2 and KOAc in DMF at 120 °C affords 4-aryl-2-quinolones in allowable to good yields.

Regio- and diastereoselective synthesis and X-ray structure determination of (+)-2-deoxyoryzalexin S from (+)-podocarpic acid. Structural nonidentity with its nominal natural isolated enantiomer

(+)-2-Deoxyoryzalexin S (1), the nominal enantiomer of a diterpenoid isolated in Chile from Calceolaria species, was regio- and diastereoselectively synthesized from (+)-podocarpic acid. (+)-2-Deoxyoryzalexin S (1) was characterized also as its acetyl derivative, (+)-2, whose structure was confirmed by X-ray crystallographic analysis. Surprisingly, comparison of the data recorded for (+)-1 and (+)-2 and those reported in the literature for the Calceolaria isolated diterpenoid 1 and its derivative (-)-2 showed some differences, suggesting that the latter do not possess the proposed structures.